Department of Psychiatry, University of Toronto and Schizophrenia Program, Centre for Addiction and Mental Health,
Toronto, Ont.

Abstract

The introduction of a number of new antipsychotics in the last decade has generated considerable excitement regarding the treatment of schizophrenia and related psychotic conditions. Clinically, it has produced changing expectations regarding treatment outcome, while academically it has encouraged a re-evaluation and expansion of theories of the pathophysiology of schizophrenia and antipsychotic activity. In this review, the development of antipsychotics is traced, beginning with chlorpromazine’s introduction in the early 1950s, and followed to the present. Despite 50 years of use and a plethora of antipsychotics available worldwide, our conceptualization of their major mode of action remains essentially unchanged. It was shortly after their development that attention turned to the importance of dopamine, and in particular the dopamine D2 receptor. Current thinking has elaborated on this model, with serotonin and glutamate receiving the greatest attention most recently, but D2 antagonism remains the sine qua non of antipsychotic activity. Although the notion of “atypical” remains somewhat of a moving target, we do have at our disposal a new generation of antipsychotics that reflect a different clinical profile from their conventional counterparts. The precise degree of these differences and the underlying mechanisms remain unclear, however. The direction new antipsychotic development takes will undoubtedly hinge on answers to these questions.

Acknowledgements: I thank Dr. Shitij Kapur for his ongoing collaboration, which is reflected in numerous aspects of this manuscript.

Competing interests: Dr. Remington is a consultant for Janssen, Eli Lilly, Pfizer, AstraZeneca, Novartis and Bristol-Myers Squibb; has received honoraria for PET research from Janssen, Eli Lilly, Pfizer and AstraZeneca; and has received speaker fees from Janssen, Eli Lilly, AstraZeneca, Pfizer and Novartis.